1. Field of the Invention
The present invention relates to a method for binding free and conjugated bile acids in warm-blooded animals, e.g. humans, and more particularly, to a method for compensating for the propensity of warm-blooded animals to generate deleterious amounts of free and conjugated bile acids present in the stomach thereof as a result of duodenogastric regurgitation.
As used herein, the term "bile acids," unless otherwise indicated, always refers to free and conjugated bile acids.
2. Description of the Prior Art
Because it is thought that the gastric ulcer, and by gastric ulcer is meant an ulcer located in the stomach as opposed to other portions of the gastrointestinal tract, is caused primarily by the action of ulcerogenic factors such as hydrochloric acid and pepsin which disturb the mucous membrane forming the inner lining of the stomach, conventional pharmaco-therapeutico efforts aimed at the treatment of gastric ulcers have heretofore concentrated on controlling the action of hydrochloric acid and pepsin. Specifically, prior known methods for treating the gastric ulcer have been essentially directed toward the inhibition of gastrointestinal motility and secretion, the blocking of spasm and the neutralization or counteraction of hydrochloric acid in the gastric juice. Additionally, there further exists one school of thought contending that the gastric ulcer is caused by abnormal action of the central nervous system, and accordingly, treatment by means of various sedatives and/or tranquilizers has been proposed; however, there is virtual concensus that hyperacidity and particularly, hyperchlorohydria, i.e., hypersecretion of hydrochloric acid in the stomach, plus the presence of gastric pepsin are primarily responsible for the formation of the gastric ulcer.
Normally, the mucosal tissues of the stomach are protected by a film of mucin, the mucopolysaccharide secreted by the gastric mucosa. It has been theorized that this agent disturbs the mucous membrane of the stomach, thereby giving rise to the formation of ulcers. Accordingly, in the past, the proposed methods of treating the condition known as the gastric ulcer has primarily focused totally on counterbalancing the effect of excess hydrochloric acid together with other mineral acids and pepsin. Those modes of treatment which have been previously employed can be generally classified as follows:
(1) Application of antacid agents for the purpose of neutralizing excess hydrochloric acid, such agents including conventional inorganic basic salts, colloidal neutralizing agents, anion exchange resin, amino acids, carboxymethylcellulose, etc.; PA1 (2) Application of anticholinergic agents; PA1 (3) The use of absorbents and adsorbents; and PA1 (4) Introduction of agents to protect the mucous membrane of the stomach, per se. PA1 Pyridine PA1 Methylnicotinate PA1 Ethylnicotinate PA1 Trimethylamine PA1 Triethylamine PA1 Methylimidazole PA1 1,4-Diazabicyclo[2.2.2.]octane PA1 Nicotinamide PA1 N-ethylnicotinamide PA1 (1) 1-.alpha.-(Benzoyloxymethyl)-3-carbamoyl-pyridinium chloride PA1 (2) 1-(Benzoyloxybenzyl)-3-carbamoyl-pyridinium bromide PA1 (3) 1-(Cinnamoyloxymethyl)-3-carbamoyl-pyridinium chloride PA1 (4) 1-(.alpha.-Benzoyloxyethyl)-3-carbamoyl-pyridinium chloride PA1 (5) 1-(.alpha.-Cinnamoyloxyethyl)-3-carbamoyl-pyridinium chloride PA1 (6) 1-(Benzoyloxymethyl)-ethylnicotinate chloride PA1 (7) 1-(Cinnamoyloxymethyl)-ethylnicotinate chloride PA1 (8) 1-(.alpha.-Benzoyloxybenzyl)-ethylnicotinate chloride PA1 (9) 1-(.alpha.-Cinnamoyloxybenzyl)-ethylnicotinate chloride PA1 (10) Benzoyloxymethyl-triethylammonium chloride PA1 (11) .alpha.-Benzoyloxybenzyl-triethylammonium bromide PA1 (12) Cinnamoyloxymethyl-triethylammonium chloride PA1 (13) .alpha.-Benzoyloxyethyl-triethylammonium chloride PA1 (14) .alpha.-Cinnamoyloxyethyl-triethylammonium chloride PA1 (15) .omega.-(Diethyl-benzoyloxymethyl-ammonium)-2,6-dimethylacetanilide chloride PA1 (16) .omega.-(Diethyl-.alpha.-benzoyloxybenzyl-ammonium)-2,6-dimethylacetanilid e chloride PA1 (17) .omega.-(Diethyl-cinnamoyloxymethyl-ammonium)-2,6-dimethylacetanilide chloride PA1 (18) .omega.-[Diethyl-(.alpha.-benzoyloxyethyl)-ammonium]-2,6-dimethylacetanili de chloride PA1 (19) .omega.-[Diethyl-(.alpha.-cinnamoyloxyethyl)-ammonium]-2,6-dimethylacetani lide chloride PA1 (20) N,N-dimethylglycine methyl ester-N-benzoyloxymethyl chloride PA1 (21) N,N-diethylglycine ethyl ester-N-benzoyloxymethyl chloride PA1 (22) .omega.-(Diethyl-pivaloyloxymethyl-ammonium)-2,6-dimethylacetanilide chloride PA1 (23) N,N-dimethylglycine methyl ester-N-pivaloyloxymethyl chloride PA1 (24) N,N-diethylglycine pyridine methanol ester-N-pivoyloxymethyl chloride PA1 (1) n-Octanoyloxymethylpyridinium chloride. PA1 (2) n-Dodecanoyloxymethylpyridinium chloride. PA1 (3) n-Tetradecanoyloxymethylpyridinium chloride. PA1 (4) n-Hexadecanoyloxymethylpyridinium chloride. PA1 (5) 1-n-Dodecanoyloxymethyl-3-methylimidazolium chloride. PA1 (6) 1-n-Tetradecanoyloxymethyl-3-methylimidazolium chloride. PA1 (7) 1-n-Hexadecanoyloxymethyl-3-methylimidazolium chloride. PA1 (8) n-Dodecanoyloxymethyltriethylammonium chloride. PA1 (9) 1-n-Dodecanoyloxymethyl-1,4-diazabicyclo [2.2.2.] octane chloride. PA1 (10) 1-n-Dodecanoyloxymethyl-N-ethylnicotinamide chloride. PA1 (11) n-Octanoyloxymethyl-3-methylimidazolium chloride or bromide. PA1 (12) n-Octanoyloxymethyl-trimethylammonium chloride or bromide. PA1 (13) n-Octanoyloxymethyl-nicotinamide chloride or bromide. PA1 (14) 1-n-Octanoyloxymethyl-ethylnicotinate chloride or bromide. PA1 (15) 1-n-Octanoyloxymethyl-methylnicotinate chloride or bromide. PA1 (16) n-Octanoyloxymethyl-triethylammonium chloride or bromide. PA1 (17) n-Decanoyloxymethyl-3-methylimidazolium chloride or bromide. PA1 (18) 1-n-Decanoyloxymethyl-pyridinium chloride or bromide. PA1 (19) n-Decanoyloxymethyl-trimethylammonium chloride or bromide. PA1 (20) n-Decanoyloxymethyl-triethylammonium chloride or bromide. PA1 (21) 1-n-Decanoyloxymethyl-nicotinamide chloride or bromide. PA1 (22) 1-n-Decanoyloxymethyl-ethylnicotinate chloride or bromide. PA1 (23) n-Dodecanoyloxymethyl-triethylammonium chloride or bromide. PA1 (24) n-Tetradecanoyloxymethyl-trimethylammonium-chloride or bromide. PA1 (25) n-Tetradecanoyloxymethyl-triethylammonium-chloride or bromide. PA1 (26) 1-n-Tetradecanoyloxymethyl-nicotinamide chloride or bromide. PA1 (27) 1-n-Tetradecanoyloxymethyl-ethylnicotinate chloride or bromide. PA1 (28) 1-n-Tetradecanoyloxymethyl-methylnicotinate chloride or bromide. PA1 (29) 1-n-Tetradecanoyloxymethyl-3-methylimidazolium chloride or bromide. PA1 (30) n-Tetradecanoyloxymethyl-1,4-diazabicyclo [2.2.2.] octane chloride or bromide. PA1 (31) 1-[.alpha.-(n-Octanoyloxy(ethyl]-pyridinium chloride or bromide. PA1 (32) 1-[.alpha.-(n-Octanoyloxy)ethyl]-3-methylimidazolium chloride or bromide. PA1 (33) .alpha.-(n-Octanoyloxy)ethyl-trimethylammonium chloride or bromide. PA1 (34) 1-[.alpha.-(n-Octanoyloxy)ethyl]-nicotinamide chloride or bromide. PA1 (35) 1-[.alpha.-(n-Octanoyloxy)ethyl]-N-ethylnicotinamide chloride or bromide. PA1 (36) 1-[.alpha.-(n-Octanoyloxy)ethyl]-ethylnicotinate chloride or bromide. PA1 (37) 1-[.alpha.-(n-Decanoyloxy)ethyl]-pyridinium chloride or bromide. PA1 (38) 1-[.alpha.-(n-Decanoyloxy)ethyl]-3-methylimidazolium chloride or bromide. PA1 (39) .alpha.-(n-Decanoyloxy)ethyl-trimethylammonium chloride or bromide. PA1 (40) .alpha.-(n-Decanoyloxy)ethyl-triethylammonium chloride or bromide. PA1 (41) 1-[.alpha.-(n-Decanoyloxy)ethyl]-nicotinamide chloride or bromide. PA1 (42) 1-[.alpha.-(n-Decanoyloxy)ethyl]-N-ethylnicotinamide chloride or bromide. PA1 (43) 1-[.alpha.-(n-Decanoyloxy)ethyl]-ethylnicotinate chloride or bromide. PA1 (44) 1-[.alpha.-(n-Decanoyloxy)ethyl]-1,4-diazabicyclo [2.2.2.] octane chloride or bromide. PA1 (45) 1-[.alpha.-(n-Dodecanoyloxy)ethyl]-pyridinium chloride or bromide. PA1 (46) .alpha.-(n-Dodecanoyloxy)ethyl-trimethylammonium chloride or bromide. PA1 (47) .alpha.-(n-Dodecanoyloxy)ethyl-triethylammonium chloride or bromide. PA1 (48) 1-[.alpha.-(n-Dodecanoyloxy)ethyl]-nicotinamide chloride or bromide. PA1 (49) 1-[.alpha.-(n-Dodecanoyloxy)ethyl]-3-methylimidazolium chloride or bromide. PA1 (50) 1-[.alpha.-(n-Dodecanoyloxy)ethyl]-N-ethylnicotinamide chloride or bromide. PA1 (51) 1-[.alpha.-(n-Hexadecanoyloxy)ethyl]-pyridinium chloride or bromide. PA1 (52) .alpha.-(n-Hexadecanoyloxy)ethyl-trimethylammonium chloride or bromide. PA1 (53) .alpha.-(n-Hexadecanoyloxy)ethyl-triethylammonium chloride or bromide. PA1 (54) 1-[.alpha.-(n-Hexadecanoyloxy)ethyl]-nicotinamide chloride or bromide. PA1 (55) 1-[.alpha.-(n-Hexadecanoyloxy)ethyl]-3-methylimidazolium chloride or bromide. PA1 (56) 1-[.alpha.-(n-Hexadecanoyloxy)ethyl]-N-ethylnicotinamide chloride or bromide. PA1 (57) 1-[.alpha.-(n-Hexadecanoyloxy)ethyl]-ethylnicotinate chloride or bromide. PA1 (58) 1-Oleyloxymethyl-pyridinium chloride or bromide. PA1 (59) Oleyloxymethyl-trimethylammonium chloride or bromide. PA1 (60) Oleyloxymethyl-triethylammonium chloride or bromide. PA1 (61) 1-Oleyloxymethyl-nicotinamide chloride or bromide. PA1 (62) 1-Oleyloxymethyl-N-ethylnicotinamide chloride or bromide. PA1 (63) 1-Oleyloxymethyl-ethylnicotinate chloride or bromide. PA1 (64) 1-Oleyloxymethyl-3-methylimidazolium chloride or bromide.
In accordance with the present invention, an entirely novel approach to the treatment of gastric ulcers in warm-blooded animals is provided, in view of the recent evidence.sup.1 that hyperchlorohydria may, in fact, not be the primary causative agent of gastric ulcers. Apparently, it now appears that the reflux of duodenal contents, and especially bile, is an important etiologic factor in the formation of gastric ulcers. It has been determined that the stomach of a patient with a gastric ulcer contains bile more frequently and at higher concentrations than that which is found in the stomach of a normal subject. In an effort to explain this phenomenon, studies have shown that in normal subjects, the pylorus functions as a sphincter which has the capacity to prevent retrograde movement of duodeno contents into the stomach. For example, the human pylorus is associated with a zone of high pressure that relaxes with antral peristalsis, contracts with endogenous or exogenous hormonal stimulation, and generally regulates the regurgitation of duodenal contents into the stomach. It appears, therefore, that the failure or malfunction of the pylorus to function in its known capacity as an effective sphincter in certain individuals, gives rise to the elevated gastric bile acid levels in the stomach, and accordingly, renders such individual prone to gastric ulcers. FNT 1. Fisher, et al., The New England Journal of Medicine, 288, No. 6, pp. 273-276 (Feb. 8, 1973).
The present invention provides a method, entirely novel in its approach to the treatment of the ulcer condition, which method is directed toward counteracting the elevated levels of gastric bile acids caused by the aforementioned pyloric incompetence.